Effects of Opioids in Cancer Pain: An Interplay Among Genetic Factors, Immune Response, and Clinical Outcomes—A Scoping Review
Simple Summary
Abstract
1. Introduction
2. Methodology
3. Pain Perception, Opioid Use, and Survival
4. Refractory Cancer Pain: Mechanisms and Consequences
4.1. Mechanisms Affecting the Response to Analgesics
4.2. Consequences of Pain Refractory Pain to Conventional Treatment
5. Immunosuppression Due to Opioid Treatment
6. Genetic Profiling
6.1. OPRM1, OPRD1, and OPRK1 Genes
6.2. NOP Gene of the Nociceptin/Orphanin FQ Receptor
6.3. CACNA1B Gene
6.4. BCL2 and BAX (Apoptosis-Related Genes)
6.5. FAAH (Fatty Acid Amide Hydrolase) Gene
6.6. KCNJ6 (GIRK2) Gene
6.7. CYP3A4 (Cytochrome P450 3A4) Gene
6.8. CYP3A5 (Cytochrome P450 3A5) Gene
6.9. CYP2C19 (Cytochrome P450 2C19) Gene
6.10. UGT2B7 (UDP Glucuronosyltransferase Family 2 Member B7) Gene
6.11. COMT (Catechol-O-Methyltransferase) Gene
6.12. ABCB1 (ATP-Binding Cassette Sub-Family B Member-1) Gene
6.13. SLC6A3 and SLC6A4 (Solute Carrier Family 6 Member 3 and 4) Gene
6.14. DRD2 (Dopamine Receptor D2) Gene
6.15. NLRs (NOD-like Receptors) Gene
6.16. PTGS2 (Prostaglandin-Endoperoxide Synthase 2) Gene
7. Clinical Applications and Treatment Implications
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Category | Gene/ Citation | Role | Impact on Pain Perception | Effect on Analgesic Drugs |
---|---|---|---|---|
Opioid Signaling Pathway | OPRM1 OPRD1 OPRK1 | Encode classical opioid receptors μ-, δ-, and κ-, mediating opioid analgesic effects. | Variations may lead to differences in analgesic efficacy and pain control. | Influence opioid responsiveness, potentially causing inadequate pain relief or increased sensitivity. |
NOP | Encodes nociceptin/orphanin FQ receptor, involved in non-classical opioid signaling. | Modulates nociceptive neurotransmission, reducing pain perception. | Potential target for novel analgesics with fewer side effects compared to traditional opioids. | |
Pain Perception Modulators | CACNA1B | Encodes N-type calcium channel subunit, critical for neurotransmitter release. | Overexpression enhances pain sensation; linked to hyperalgesia. | Genetic variants may alter opioid efficacy; dysfunction affects analgesic responses. |
BCL2 BAX | Regulate cellular apoptosis; BCL2 gene is anti-apoptotic, while BAX is pro-apoptotic. | Imbalance increases neuronal sensitivity to pain. | Targeting these pathways may reduce pain and modulate glial activation. | |
FAAH | Enzyme degrading endocannabinoids, particularly anandamide. | Inhibition increases anandamide levels, reducing pain sensitivity. | FAAH 1 inhibitors may enhance analgesic effects; polymorphisms affect treatment responses. | |
KCNJ6 | Encodes GIRK2 2 potassium channels, regulating neuronal excitability. | Variants influence pain sensitivity and opioid requirements. | Genetic variants may necessitate opioid dosage adjustments for effective analgesia. | |
Drug Metabolism Genes | CYP2D6 CYP2B6 CYP3A4 CYP3A5 CYP2C19 | Enzymes involved in Phase I drug metabolism, including opioids. | No direct influence on pain perception. | Variants affect opioid metabolism, altering efficacy and risk of side effects like toxicity or inadequate relief. |
UGT2B7 | Enzyme responsible for Phase II glucuronidation of opioids like morphine. | No direct influence on pain perception. | Polymorphisms impact opioid efficacy by altering metabolite levels; dosage adjustments may be required. | |
COMT | Metabolizes catecholamines, affecting neurotransmitter levels. | Polymorphisms influence pain sensitivity and stress response. | Variants affect opioid dosage requirements; specific genotypes need higher or lower doses for effective pain control. | |
Transport and Regulatory Genes | ABCB1 | Encodes P-glycoprotein, an efflux transporter affecting drug distribution and blood-brain barrier crossing. | Variants influence nociceptive processing and pain sensitivity. | Alters opioid transport, affecting drug efficacy and toxicity. |
SLC6A3 SLC6A4 | Encode dopamine and serotonin transporters, regulating synaptic neurotransmitter levels. | Polymorphisms may influence pain modulation and emotional responses. | May affect efficacy of drugs modulating serotonergic or dopaminergic systems. | |
DRD2 | Encodes dopamine D2 receptor, involved in dopaminergic signaling. | Variants affect pain sensitivity and stress responses. | May influence opioid efficacy and risk of addiction. | |
NLRs | Encode NOD-like receptors 3, involved in immune and inflammatory responses. | Activation amplifies nociceptive signaling through pro-inflammatory cytokines. | Potential therapeutic targets for reducing opioid tolerance and opioid-induced hyperalgesia. | |
Inflammatory Response Gene | PTGS2 | Encodes COX-2 4, essential for prostaglandin synthesis in inflammatory responses. | Variants linked to heightened pain sensitivity and inflammation. | Target for NSAIDs 5; polymorphisms may affect anti-inflammatory drug efficacy. |
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Adamczyk, K.; Zuzda, K.; Jankowski, M.; Świerczyński, R.; Chudziński, K.; Czapski, B.; Szułdrzyński, K. Effects of Opioids in Cancer Pain: An Interplay Among Genetic Factors, Immune Response, and Clinical Outcomes—A Scoping Review. Cancers 2025, 17, 863. https://doi.org/10.3390/cancers17050863
Adamczyk K, Zuzda K, Jankowski M, Świerczyński R, Chudziński K, Czapski B, Szułdrzyński K. Effects of Opioids in Cancer Pain: An Interplay Among Genetic Factors, Immune Response, and Clinical Outcomes—A Scoping Review. Cancers. 2025; 17(5):863. https://doi.org/10.3390/cancers17050863
Chicago/Turabian StyleAdamczyk, Kamil, Konrad Zuzda, Miłosz Jankowski, Rafał Świerczyński, Kamil Chudziński, Bartosz Czapski, and Konstanty Szułdrzyński. 2025. "Effects of Opioids in Cancer Pain: An Interplay Among Genetic Factors, Immune Response, and Clinical Outcomes—A Scoping Review" Cancers 17, no. 5: 863. https://doi.org/10.3390/cancers17050863
APA StyleAdamczyk, K., Zuzda, K., Jankowski, M., Świerczyński, R., Chudziński, K., Czapski, B., & Szułdrzyński, K. (2025). Effects of Opioids in Cancer Pain: An Interplay Among Genetic Factors, Immune Response, and Clinical Outcomes—A Scoping Review. Cancers, 17(5), 863. https://doi.org/10.3390/cancers17050863